Pharmacokinetics of Direct Brain Infusion. Distribution of therapeutic agents in the central nervous system (CNS) with currently available delivery techniques is problematic. An approach that our colleagues and we developed to overcome the obstacles associated with current CNS drug delivery techniques is convective delivery, which uses bulk flow to enhance distribution. Our studies have demonstrated that convection-enhanced delivery to the brain, brainstem, spinal cord, and peripheral nerve in large and small animals can be used to distribute macromolecules in a homogenous, targeted, and safe manner and with clinically effective Vd. Recent efforts have focused on determining the factors that optimize convection-enhanced delivery into the brain, brainstem, spinal cord, and peripheral nerve. To further our understanding of the variables that affect convective delivery we are examining the effect of particle size on distribution in brain, brainstem, spinal cord, and peripheral nerves. High-flow interstitial infusion is being used to deliver various agents, such as immunotoxins, genetic vectors, and chemotherapeutic molecules in the investigation of treatment of various disorders of the central nervous system. We have developed new imaging contrast agents for non-invasively monitoring infusion volume of distribution and concentration for CT and MRI. Neurotoxicity testing of these imaging agents revealed no evidence of neuronal degeneration up to three months after infusion in rat and primate brains. Thus, we have demonstrated the utility of these imaging agents for real-time, non-invasive monitoring of the distribution of therapeutic agents during infusion of macromolecular drugs. Clinical investigations are occurring including direct convective delivery of chemotherapeutic agents to the brainstem for the treatment of brainstem gliomas and glucocerebrosidase for the treatment of neuronopathic Gaucher disease.[unreadable] [unreadable] The hippocampus is the usual site of origin of medically intractable epilepsy. Relief of this type of epilepsy could occur if a method were developed to selectively suppress the epileptic focus within the hippocampus. After success in ablating seizures in a rodent model using convective perfusion of the epileptic focus, our laboratory conducted a study of the toxicity and distribution of the chronic infusion of muscimol into the hippocampus of 10 non-human primates. Depth electrode studies showed that electrical activity in the hippocampus could be suppressed by muscimol. Autoradiography of infused muscimol demonstrated that muscimol could be delivered to the entire hippocampus using convective perfusion. The infusions were tolerated without brain injury or permanent adverse effects. The FDA granted us in May 2006 approval of IND 60,518 for intracerebral convection-enhanced delivery of muscimol to brain. Candidates for seizure surgery are being recruited for our clinical study (Protocol 00-N-0158) of the infusion of muscimol into the hippocampus to temporarily inactivate the neurons of the epileptic focus. If this is successful, we will explore if other agents can be used to permanently and selectively inactivate the epileptic focus. In an ongoing clinical study of patients with medically intractable epilepsy (Protocol 02-N-0014), temporal lobe tissue specimens that were removed to treat medically intractable epilepsy associated with mesial temporal sclerosis were subjected to extensive histological and virological evaluation. This evaluation demonstrated that medial temporal lobe tissue from some of these patients had elevated levels of human herpesvirus type 6 (HHV-6), suggesting a role for this virus in this chronic condition.